In a commentary recently published in the Journal of Alzheimer’s Disease, Ian Clark and Craig Atwood discussed some novel mechanisms and viewpoints related to the “cross-talk” between tumor necrosis factor (TNF) and endocrine dyscrasia, and how this might affect the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD), stroke and traumatic brain disease.
Endocrine dyscrasia is an age-related dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis and is associated with dyotic signaling and the induction of neurodegenerative cascades within the brain.
These endocrine changes, and particularly, the elevation of gonadotropins concentrations and the loss of sex steroid signaling, have been recently linked to the development of Alzheimer’s disease (AD). Current evidence also indicates that in AD, the inflammation (and thus, the expression of pro-inflammatory cytokines) is most likely an early step that initiates the disease rather than a late step that minimizes the disease.
In the Journal of Alzheimer’s Disease commentary, Ian Clark and Craig Atwood suggest that both the loss of sex steroids/inhibins and the elevation of GnRH/gonadotropins with age-related endocrine dyscrasia, would serve to elevate TNF expression in the brain.
According to the authors, better understanding of these widespread functional links between the gonadotropins, sex steroids, and TNF may provide further insights into the pathogenesis of, and therapy for neurodegenerative diseases.
SOURCE: J Alzheimers Dis 2011, Sep 2. [Epub ahead of print]
Updates
A 2017 review published in the journal Current Alzheimer Research concludes that TNF-α plays a pivotal role in inflammation, thus, it is a very attractive pharmacological target. Accordingly, pre-clinical data indicate that increased TNF-α levels exacerbates amyloidogenesis, and diverse paradigms used to reduce TNF-α signaling in rodent models of AD indicate significant reduction in AD-like brain pathology accompanied by an amelioration of cognitive function. Therefore, as per the authors, TNF-α inhibition to prevent or slow AD should be explored in more depth in clinical trials.
A large 2020 retrospective case-control study published in PLOS One used the electronic health records from 56 million unique adult patients. The study examined whether or not treatment with a TNF blocking agent is associated with lower risk for Alzheimer’s disease (AD) in patients with rheumatoid arthritis (RA), psoriasis, and other inflammatory diseases.
The risk for AD in patients with RA was lower among patients treated with etanercept, adalimumab, or infliximab. Etanercept and adalimumab also were associated with lower risk for AD in patients with psoriasis.
This study identifies a subset of patients in whom systemic inflammation contributes to risk for AD through a pathological mechanism involving TNF and who therefore may benefit from treatment with a TNF blocking agent.
In conclusion, patients diagnosed with a systemic inflammatory disease are at increased risk for developing AD, while TNF blocking agents were associated with decreased risk for co-morbid AD in real-world patients diagnosed with RA or psoriasis.
A 2021 study published in Acta Neuropathologica Communications indicates that the neuronal loss in AD is due to TNF-mediated necroptosis rather than apoptosis, which is amenable to therapeutic intervention at several points in the signaling pathway.
Overall, this study demonstrates a link between TNF signaling via TNFR1 and necroptosis activation and neuronal loss in the AD hippocampus using human post-mortem brain tissues. This was recapitulated in vitro in human iPSC-derived glutamatergic neurons treated with TNF when apoptosis was inhibited.
In addition, the authors report that small molecule inhibitors against RIPK1, RIPK3, and MLKL could significantly protect human cortical neurons against TNF-mediated necroptotic cell death in vivo; And, also related changes in the ESCRT-III pathway components in the AD hippocampus. These findings provide new insights into the involvement of TNF signaling and necroptosis in neurodegeneration in AD.
A 2023 narrative review summarizes the evidence in relation to the involvement of TNF-α in AD and its possible therapeutic inhibition. Thus, several studies report that patients with RA and systemic inflammatory diseases treated with TNF-α blocking agents reduce the probability of emerging dementia compared with the general population. An increasing amount of basic scientific data and clinical studies underscore the importance of inflammatory processes and subsequent glial activation in the pathogenesis of AD. TNF-α targeted therapy is a biologically plausible approach for cognition preservation and further trials are necessary to investigate the potential benefits of therapy in populations at risk of developing AD.
In general, the evidence collected so far suggests that TNF-α impacts various neuronal activities, including modulation of neurotransmission, sleep regulation, and astrocyte-mediated glutamate release. TNF-α is a key molecule in orchestrating chronic inflammation and can influence the synthesis of Aβ plaques, and the formation of neurofibrillary tangles and therefore can curb the progression of AD pathology. Clinical trials exploring the effects of TNF-α inhibitors in the development and progression of AD hold interesting results. Interesting data also came from the investigation of several molecules characterized by TNF-α inhibition in animal models of AD. These results show promising evidence to target disease progression by addressing different inflammatory pathways induced by TNF-α.
A 2024 study published in the Open Access journal MDPI reports that TNF-α levels are increased in patients with subjective cognitive impairment. The authors analyzed plasma TNF-α and Aβ42 levels in patients with subjective cognitive impairment (SCI), mild cognitive impairment (MCI), and AD, and in healthy volunteers (HLT). In addition, they performed correlation analysis to evaluate whether changes in plasma TNF-α levels correlate with cognitive decline, Aβ42 levels, age, and BMI, which are all factors considered to contribute to or predispose individuals to AD.
The researchers found that TNF-α and Aβ42 plasma levels were higher in patients with AD than in HLT individuals. High TNF-α levels were also observed in patients with SCI, in whom TNF-α and Aβ42 levels were negatively correlated. Of note, TNF-α did not affect the amyloidogenic pathway in human microglial cultures exposed to 48 h of incubation, although it did trigger neuroinflammatory processes. Thus, the authors conclude that high TNF-α levels are more likely to be a clinical condition linked to AD than are direct contributors.
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